Genetic Variant NM_001626.6:c.-480G>C (chr19-40285576-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001626.6(AKT2):c.-480G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 372,500 control chromosomes in the GnomAD database, including 7,642 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4368 hom., cov: 31)

Exomes 𝑓: 0.17 ( 3274 hom. )

Consequence

AKT2
NM_001626.6 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.122

Publications

5 publications found

Variant links:

Genes affected

AKT2 (HGNC:392): (AKT serine/threonine kinase 2) This gene is a putative oncogene encoding a protein belonging to a subfamily of serine/threonine kinases containing SH2-like (Src homology 2-like) domains, which is involved in signaling pathways. The gene serves as an oncogene in the tumorigenesis of cancer cells For example, its overexpression contributes to the malignant phenotype of a subset of human ductal pancreatic cancers. The encoded protein is a general protein kinase capable of phophorylating several known proteins, and has also been implicated in insulin signaling. [provided by RefSeq, Nov 2019]

AKT2 Gene-Disease associations (from GenCC):

hypoinsulinemic hypoglycemia and body hemihypertrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
AKT2-related familial partial lipodystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
type 2 diabetes mellitus
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

AKT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
AKT2	NM_001626.6 link	c.-480G>C	upstream_gene_variant	ENST00000392038.7	NP_001617.1	P31751-1
AKT2	NM_001243027.3 link	c.-629G>C	upstream_gene_variant		NP_001229956.1	B4DG79
AKT2	NM_001243028.3 link	c.-536G>C	upstream_gene_variant		NP_001229957.1	B4DG79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT2	ENST00000392038.7 link	c.-480G>C		upstream_gene_variant		1	NM_001626.6	ENSP00000375892.2		P31751-1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

32925

AN:

152004

Hom.:

4351

Cov.:

show subpopulations

Gnomad AFR

AF:

0.367

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.137

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.200

GnomAD4 exome

AF:

0.166

AC:

36608

AN:

220378

Hom.:

3274

Cov.:

AF XY:

0.165

AC XY:

18502

AN XY:

112178

show subpopulations

African (AFR)

AF:

0.368

AC:

2319

AN:

6300

American (AMR)

AF:

0.127

AC:

828

AN:

6512

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

1345

AN:

8162

East Asian (EAS)

AF:

0.153

AC:

3144

AN:

20550

South Asian (SAS)

AF:

0.104

AC:

209

AN:

2000

European-Finnish (FIN)

AF:

0.201

AC:

3933

AN:

19570

Middle Eastern (MID)

AF:

0.150

AC:

171

AN:

1140

European-Non Finnish (NFE)

AF:

0.156

AC:

22061

AN:

141664

Other (OTH)

AF:

0.179

AC:

2598

AN:

14480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1382

2764

4147

5529

6911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.217

AC:

32982

AN:

152122

Hom.:

4368

Cov.:

AF XY:

0.215

AC XY:

15961

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.367

AC:

15235

AN:

41476

American (AMR)

AF:

0.160

AC:

2453

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

573

AN:

3472

East Asian (EAS)

AF:

0.137

AC:

711

AN:

5174

South Asian (SAS)

AF:

0.105

AC:

508

AN:

4826

European-Finnish (FIN)

AF:

0.195

AC:

2068

AN:

10590

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.158

AC:

10729

AN:

67972

Other (OTH)

AF:

0.199

AC:

420

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1258

2516

3775

5033

6291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.200

Hom.:

442

Bravo

AF:

0.221

Asia WGS

AF:

0.138

AC:

481

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.2

(source)

DANN

Benign

0.47

PhyloP100

0.12

PromoterAI

-0.048

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over